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Abstract Number: 1071

A Common Transcriptional Signature Is Present in Circulating Classical Monocytes and Skin Macrophages in Systemic Sclerosis

Hadijat Makinde1, Salina Dominguez 2, Gaurav Gadhvi 3, Kathleen Aren 4, Chang Zeng 3, Garrett Eickelberg 3, Dinesh Khanna 5, Shervin Assassi 6, Tracy Frech 7, Monique Hinchcliff 8, Carla Cuda 9, Deborah Winter 2 and Harris Perlman 2, 1Northwestern University, Chicago, IL, 2Northwestern University Feinberg School of Medicine, Division of Rheumatology, Chicago, 3Northwestern University, Chicago, 4Northwestern.edu, Chicago, 5Scleroderma Program, Division of Rheumatology, Department of Internal Medicine, Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, 6Division of Rheumatology and Clinical Immunogenetics, University of Texas McGovern Medical School, Houston, Texas, USA, Houston, TX, 7Division of Rheumatology, University of Utah and Salt Lake VAMC, Salt Lake City, UT, 8Yale University, Section of Rheumatology, Allergy and Immunology, New Haven, CT, 9Northwestern University Feinberg School of Medicine, Division of Rheumatology, Chicago, IL

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Classical Monocytes, Skin Macrophages and Autoimmune Skin Disease, SS-RNA-Seq, ssc

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Session Information

Date: Monday, November 11, 2019

Title: Systemic Sclerosis & Related Disorders – Basic Science Poster

Session Type: Poster Session (Monday)

Session Time: 9:00AM-11:00AM

Background/Purpose: The etiology and pathogenesis of systemic sclerosis (SSc) are poorly understood; however, an increasing body of evidence supports an early inflammatory phase that precedes fibrosis. Circulating monocytes likely play a critical role in SSc progression through secretion of pro-inflammatory molecules and as precursors of macrophages that can reorganize the extracellular matrix (ECM) to leading to the development of end-organ fibrosis. Here we evaluate the transcriptional similarities between circulating classical monocytes and macrophages present in the skin of SSc patients.

Methods:  Classical monocytes (CMo) were sorted using multiparameter fluorescence-activated cell sorting (FACS) from early diffuse cutaneous (dc) SSc sample blood obtained through the Prospective Registry of Early Systemic Sclerosis (PRESS) cohort. Bulk RNA-seq was performed, and transcriptional profiles were analyzed along with age-, sex-, and ethnicity-matched controls.  Additionally, CD45+ immune cells, as well as CD31+ endothelial cells were FACS-sorted from skin biopsies of one SSc patient and one control patient and prepared for single-cell RNA-seq.

Results: There was an expansion in the skin macrophages from 36 cells in the control sample to 67 cells in the patient sample but no significant difference in the quantity (as a percent of total CD45+ cells) of circulating CMo (p=0.134) between controls and SSc patients. The differentially expressed genes in the circulating CMo were identified using DESeq2. Of the 152 significantly up-regulated genes (DESeq2, p< 0.05, Log2 Fold change in expression >1) observed in the circulating CMo population and the 290 up-regulated genes (Log2 Fold change in expression >1) found in the skin macrophage cluster compared to their respective controls, we find 23 genes in common (p< 1.23×10-8, hypergeometric distribution test). These shared genes are involved in processes that include ‘inflammatory response’ (p< 6.56×10-4, IL10, IL8, IL1B, CXCR4), ‘regulation of mononuclear cell proliferation’ (p< 7.65×10-5, IL1B, IL10, MNDA, PNP), ‘dendritic cell migration’ (p< 5.07×10-4, GPR183, CXCR4), ‘cytokine-mediated signaling pathway’ (p< 1.68×10-5, IL10, VEGF, CXCR4, IFI6), ‘negative regulation of epithelial cell proliferation’ (p< 4.45×10-4, RGCC, THBS1, EREG), ‘regulation of endothelial cell proliferation’ (p< 4.02×10-5, VEGFA, IL10, RGCC, THBS1).

Conclusion: These data indicate that a common transcriptional signature exists between circulating classical monocytes and macrophages present in the skin of SSc patients, potentially suggesting that macrophage-specific pathways that have gone awry at the site of fibrosis can be detected in a circulating precursor population. Future studies will focus on interrogating the penetrance of this gene signature by cross-referencing blood monocyte and skin macrophage transcriptional profiles from the same patient to determine whether this signature in circulating classical monocytes correlates with the severity of skin fibrosis and/or serves as a predictive marker of disease.


Disclosure: H. Makinde, None; S. Dominguez, None; G. Gadhvi, None; K. Aren, None; C. Zeng, None; G. Eickelberg, None; D. Khanna, Acceleron, 5, Actelion, 5, Bayer, 2, 5, Blade Therapeutics, 5, BMS, 2, 5, Boehringer Ingelheim, 5, Celegene, 5, ChemomAB, 5, Corubus, 5, CSL Behring, 5, Curzion, 5, Cytori, 5, Eicos, Inc, 4, Genentech, 5, GSK, 5, Horizon, 2, Mitsubishi Tanabe Pharma Development America, 5, Pfizer, 2, Sanofi-Aventis, 5, UCB, 5; S. Assassi, Bayer, 2, Boehringer Ingelheim, 2, 5, 8, Integrity Continuing Education, 8, 9, Medscape, 8, 9, Momenta, 2; T. Frech, None; M. Hinchcliff, None; C. Cuda, None; D. Winter, None; H. Perlman, None.

To cite this abstract in AMA style:

Makinde H, Dominguez S, Gadhvi G, Aren K, Zeng C, Eickelberg G, Khanna D, Assassi S, Frech T, Hinchcliff M, Cuda C, Winter D, Perlman H. A Common Transcriptional Signature Is Present in Circulating Classical Monocytes and Skin Macrophages in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-common-transcriptional-signature-is-present-in-circulating-classical-monocytes-and-skin-macrophages-in-systemic-sclerosis/. Accessed .
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